MicroRNA (miRNA) control has recently emerged as a critical regulator of gene expression and protein synthesis, affecting homeostasis, health and disease. No information is available on the differential occurrence of miRNAs in the gingival tissues in various states of periodontal health and disease, on the cell sub- populations that express these miRNAs, or on the functional implications of these short RNA sequences. In our earlier work supported by NICDR, we have collected specimens from clinically healthy and diseased gingival tissues from patients with chronic or aggressive periodontitis, and have studied the gingival tissue transcriptome and its association with clinical, microbiological and serological markers of periodontitis. In the first phase of the current proposal, we intent to utilize 242 available archived tissue specimens from the above study, obtained from a subset of 101 thoroughly phenotyped patients (53 with chronic and 48 with aggressive periodontitis), to examine the occurrence of miRNAs in the gingival tissues in states of periodontal health and disease and in different types of periodontal lesions. Next, we will use bio-informatics approaches to identify potential gene targets to which the identified miRNAs bind preferentially, and will validate in our own full- genome transcriptomic database whether these predicted targets were indeed down-regulated in the gingiva. We will subsequently harvest gingival tissues from de novo recruited individuals, we will identify the specific cell populations that account for the miRNAs found in the previous step to be differentially expressed in whole tissue lysates, and will confirm whether their target genes are also repressed in these cell types. Lastly, we will use a novel miRNA inhibition approach in appropriate cell culture models to begin to functionally characterize the identified miRNA sequences. The proposed studies will address a significant gap in knowledge in a cost-effective manner and in a short period of time, and will advance our understanding of the pathobiology of periodontal diseases.